The focus of this study is to elucidate the efficacy of a glucocorticoid receptor antagonist, mifepristone, on the affective and cognitive symptom profile that characterizes treatment resistant bipolar depression. Patients with bipolar depression often have indices of hypercortisolism, which potentially contribute to central nervous system dysfunction responsible for the cognitive and affective abnormalities in bipolar disorder. Recent data reveal that mifepristone is capable of ameliorating the mood and thought disturbances of psychotic depression. Clinical responsiveness to mifepristone in bipolar depression would implicate cortisol and an abnormal hypothalamic-pituitary axis (HPA) axis directly in mood abnormalities and specific cognitive deficits in bipolar depression. A detailed dissection of the HPA axis in bipolar patients should identify a distinctive mifepristone -responsive pathophysiological subtype based on neuroendocrine profile. Patients, in addition to careful clinical evaluation, will be carefully evaluated by physiologic stimuli that probe discreet aspects of HPA axis organization including diurnal rhythm, pulsatile secretion, feedback responsiveness to cortisol, and pituitary responsiveness to corticotrophin releasing hormone challenge. Patients will also receive formal neuropsychological and psychophysiological testing of various components of information processing, including those that are cortisol-dependent and associated with bipolar illness.
